Alpha-amino-beta, beta-diethoxypropionic acid and process for preparation



Patented Aug. 2, 1949 2,478,047 I C E 2,478,047 ALPHA-AMINO-BETA,BETA DIETHOXY- PROPIONIC PREPARATION Oscar H. Johnson,

Merck & 00., Inc., of New Jersey ACID AND PROCESS FOR Medina, N. Y., assignor to Rahway, N. J., a corporation No Drawing. Application February 14, 1947,

Serial No. 728,724

Claims. 1

This invention is concerned generally with novel chemical compounds, and with processes for preparing the same; more particularly it relates to a-amino- 3,5-diethoxy-propionic acid, an important intermediate in the synthesis of penicillin, and with intermediate products and processes employed in synthesizing the same from readily available starting materials. The u-amino-fi,/i-diethoxy-propionic acid is easily converted to a phenylacetamido 5,5 diethoxy propionic acid, which, upon hydrolysis yields u-formylphenaceturic acid. This compound and the esters thereof, are of value in the preparation of other organic compounds, some of which have anti-bacterial properties. These compounds may be converted into serine, an amino acid, by reduction with aluminum amalgam and hydrolysis with an acid. They may be condensed with cysteine to yield a-[2-(4-car-boxy)thiazolidinyll phenaceturic esters, and with related compounds to yield similar reaction products. Other uses of these compounds will occur to thkose skilled in the art.

It is now discovered that a-amino-p, 3- dlethoxypropionic acid can be synthesized by reactions indicated as follows:

The reactions indicated follows: ethyl u-chloro-mi-diethoXy-propionate (1), which can be prepared as described in a co-pending application belonging to applicants assignee, Serial No. 683,143, filed July 12, 1946, U. S. Patent 2,459,059, is subjected to alkaline hydrolysis to form oc-ChlOlO-flfi-diBthOXY-pIOpiOHiC acid (2); this compound is then reacted with aqueous ammonium hydroxide to produce a-amL no-pip-diethoxy-propionic acid.

oc-All'llllO-fi,,8-dlGthOXY-IJIODlOIliC acid (3) can be converted to u-phenylacetamido-fi li-diethoxypropionic acid, by reaction with phenyl acetyl chloride. When the a-phenylacetamido-p, 3-diethoxy-propionic acid is heated with acetic anhydride the product obtained is 2-benzyl-4-ethoxymethylene-5(4) -oxazolone, which can be reacted with d-penicillamine to produce penicillin G.

Details for carrying out the procedures indicated above are disclosed in copending applications Serial No. 710,945, filed November 19, 1946, Serial No. 636,516, filed December 21, 1945, and Serial N 0. 656,772, filed March 23, 1946.

above are conducted as is saponified without affecting the acetal linkages. It is preferred to employ a temperature below about 50 C. in the saponification reaction. Unsaponified matter is extracted from the aqueous alkaline reaction solution by means of a water-immiscible solvent, such as ether. The aqueous solution is then acidified with a mineral acid, such as hydrochloric acid, sulfuric acid, and the like, and the a-Ch10IO-fi,fldlethOXypropionic acid thus formed is extracted from the aqueous solution by means of a water-immiscible organic solvent, such as ether. The non-aqueous extract is then dried and the solvent evaporated therefrom to produce crude zx-ChlOlO-fifi-CiithoXy-propionic acid The crude a-chloro fifi-diethoxy-propionic acid is reacted Without further purification, at elevated temperature under pressure, with concentrated aqueous ammonium hydroxide.

reaction temperatures up to about C., if do sired. The reaction solution is evaporated to drysolvent such as ethanol, methanol and the liken a-amino-pp-diethoxy-propithe greater part of the ammonium chloride formed during the amonic acid product, whereas monolysis remains undissolved. The alcoholic. solution may be decolorized, if desired, by treat-- ment With an activated charcoal, such as Norit,. which is removed by filtration and the decolorizedi alcoholic solution evaporated to dryness.

and the filtrate is cooled, whereupon u-amino-p,p-diethoXy-propionic crystallizes therefrom as a white crystalline gran ular powder. This material can be further purifled, if desired, by recrystallization from aqueous alcohol but the purified product does not show a constant melting point.

The followin examples illustrate methods of carrying out the present invention, but it is to be understood that these examples arexgiven by Way of illustration and not of limitation.

Example 1 About thirty-six grams (:1(imols) of etliyl" 5 a-chloro-fi,,B-diethoxy-propionate are stirred" at a" temperature of about 25 C. with about 400 cc. of 0. 5. N aqueous sodium hydroxide -soluti'dn.-un-- til substantially all of the ester dissolves,.whicli requires a time of approximately ten to fifteen minutes. The aqueous alkaline solution is:.-ex'- tracted once with ether, and the aqueous layeris cooled to about 5 C. and slowly acidified by the addition thereto of approximately 100 'cc. of 2N aqueous sulfuric acid.* The aqueous acid solution is then extracted with five 150 cm'portions of ether and the ether extracts are combined'and" washed twice with cc. portions of water'and" then dried'over anhydrous sodium'sulfate." The dry etherextract is evaporated under reduced. pressure and the residual material is "dried in vacuo over phosphorus pentoxide to produce ap proximately 25 gms,- of" u-chloro-pfi-diethoxy f propionic acid; yield approximately I 85% of?" theory.- 25

Erwmple 2 A mixture containing. about 300 cc. of concentrated aqueous ammonium hydroxide (29% M13) and about fifteen grams of u-chloro-dddiethoxypropionic acid, prepared substantially as de 30 scribed in Example 1, is heated ata temperature of about 100 C.'for approximately fifteen hours in a closed vessel under pressure. The solventis evaporated from the dark reaction solution un- 4 der reduced pressure and. the residual material -3 is dissolved in about 250 cc. of hot absolute*al--- cohol. The alcoholic solution is treated-with Norit (an activated charcoalproduct), filtered; and the filtrate evaporated to dryness under rer duced pressure. extracted with about 100 cc. of absolute alcohol (dried over anhydrous calcium sulfate), under vhich conditions most of the ammoniumchloride "t formed during the ammonolysis reaction remains The residual material is again form;' which -comp'rises reacting ethyl a-chloro- {3,B-diethoxy-propionate with aqueous sodium hydroxide solution at a temperature below about C., reacting the compound thus obtained with concentrated aqueous ammonium hydroxide, said reaction being carried out by heating the reactantstog'ether under pressure at a temperature of 'approximately"100 C. for a period of at leastabout'l5 hours to produce crude (it-aminofiyi-diethoxy-propiornc acid, separating this compound I from the by-product ammonium chloride by evaporating the aqueous reaction mixture and extracting the residue with alcohol and filtering, decolorizing the alcoholic solution by treatment with activated charcoahand cooling the alcoholic solution to propionic acid.

3."The process of preparing-'- a-amino-B,g-di eth'oxy-pro'pionic acid, which comprises reacting a-chloro-{3,p-diethoxy-propionic I acid with con-- centrate'd aqueous ammonium hydroxide, said reh action being carried out by heating the-reactants together under pressure at a-temprature of approximately 100C. I p

4. The process of preparing -ami no -,B,5-diethoxy-propionic acid, in substantially pureform, which comprises reacting .a-chloro-[ifi-di ethoxy-propionic acid, at a, temperature of approximately 100" C. under pressure; and for a period of at least about 15 hours,'with concentrated aqueous ammonium hydroxide to produce;

a amino dB-diethoriy-propionic acid; separating this compound from by-product ammonium chloride by evaporating the aqueous reaction mixture and extracting the residue with alcohol and filtering; decolorizing the alcoholic solution bytrea'tinent with'activat'e'd charcoal, and cooling;

the alcoholicsolution to crystallize a-amino-fl,fidithbXY-tmropionic acid.- I 5. "a-Amino,B,fi-diethoxy-propionic a cid OSCAR I-I. JOHNSON:

nnnnniifio'iis" CITED The following references are of record in the undissolved. The alcoholic extract is filteredand .45 file of this patent:

the filtrate is cooled to approximately 05"-C.= and maintained at this temperature for a period. of about one hour. The crystalline material: which separates is recovered by filtration to proethoxy-propionic acid-which contains a trace of halogen. This product can be recrystallized if desired, employing about 30 cc. of 80% aqueous ethanol to produce substantially purea-amlno-x (depending on rate of heating). Anal.-calcd. for C'1H15O4N: C, 47.44; H, 8.53;" N, 7.91.. F0und:-C,-2- 47.65; H,8.83;' N, 8.13. Equiv. weight; Cale-dz 1'7'72. Found: 175.

Modifications may be made in carryingout the present invention without departing from the spirit andscope thereof and the inventionis to be limited. only by the appended claims."

I claim:

2,405,820... duce approximately 5.5 gins. of a-amino--fi,B-di-=5 UNITED STATES PATENTS Name Date Faith. Aug. 13, 1946 OTHER REFERENCES Wohl at a]. Ber. Deut. Chem, vol. 40 (1907), pages 93-95.

Number Oro'shnik etal. J. AmJChem. sod, voice my 1945. pages 722-v23i pagei'181'4.

Block Chemical Review," v01 3s' Jui1e--194t,

page 514.

page 1 (Sept. 27, 1945;). Upjohn. Report -V,

1. The process ofpreparing a-al'l'linO'-'fi,fi di'-'"65 (Sept. 27,1945).

ethoxy-propionic acid which comprises-reacting ethyl a-chloro-B,fl-diethoxy-propionate with an=- aqueous alkaline solution at a temperature below about 50 C., and reacting the compoundthusf obtained with concentrated aqueous ammoniumhydroxide, said reaction being carriedi out byci heating the reactants together-under pressure at a temperature of approximately; C.

2. The process of preparing -a-amin0-fifi-db MerckReport' 10, Jan. 31,1944", page 10 (Sept.

Merck Report izdiieb. 18,'1944,-page-5' (septa MerckReport l'l, Aprill'l, 1944,page 2 (Sept;

Squibb Report '8, Jani: 1944fpage (Sept; 27,

(Each 'of' the above: reports is hvailable i-n ethoxy-propionic acid, in substantially I pure (5 Div. 59.)

Wislifnus Ber. pent. -crieni.-," vol; 43 (1910) 13,,13-diethoxy-propionic acid; dec. p. -200 .C.-..55'

April 1 3} 194Lpages -24 26 

